Method of treating cancer using dithiocarbamate derivatives

Abstract

Dithiocarbamate, particularly tetraethylthiuram disulfide, and thiocarbamate anions strongly inhibit the growth of cancer cells of a variety of cell types. Such inhibitory effect is enhanced by heavy metal ions such as copper ions, cytokines and ceruloplasmin. A method is presented for using tetraethylthiuram disulfide to reduce tumor growth, and to potentiate the effect of other anticancer agents.

That which is claimed is:  
     
         1 . A method of treating cancer in humans and for sensitizing tumors to conventional cancer chemotherapy by blocking the P-glycoprotein membrane toxin extrusion pump and for sensitizing AIDS patients to anti-retroviral therapy by blocking the P-glycoprotein membrane toxin extrusion pump comprising administering a therapeutically effective amount of a dithiocarbamate thiolate an n of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are the same or different and represent hydrogen, and unsubstituted or substituted alkyl, akenyl, aryl, alkoxy, and heteroaryl groups; M is an alkali metal selected from the group consisting of from the group consisting of sodium, potassium, calcium, magnesium, barium, and lithium; and n is the valence of the alkali metal.  
     
     
         2 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is in the form of a pharmaceutically acceptable salt.  
     
     
         3 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered in a dosage of between about 125 to about 1000 mg per day of body weight.  
     
     
         4 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered in a dosage of between about 250 to about 500 mg per day.  
     
     
         5 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered parenterally.  
     
     
         6 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered orally.  
     
     
         7 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered in combination with a metal complex that includes a metal selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc, and an anion of small molecular weight.  
     
     
         8 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered in combination with a metal chelate that includes an ion selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc.  
     
     
         9 . The method according to  claim 7  wherein said metal complex is administered as a chelate with an organic anion.  
     
     
         10 . The method according to  claim 9  wherein said organic anion selected from the group consisting of citrate, acetate, glyconate, glycinate, propionate and lactate.  
     
     
         11 . The method according to  claim 1  wherein said dithiocarbamate thiolate anion is administered in combination with a metal chelate that includes an ion selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc, and an anion of small molecular weight.  
     
     
         12 . A method of treating cancer in humans and for sensitizing tumors to conventional cancer chemotherapy by blocking the P-glycoprotein membrane toxin extrusion pump and for sensitizing AIDS patients to anti-retroviral therapy by blocking the P-glycoprotein membrane toxin extrusion pump comprising administering a therapeutically effective amount of a dithiocarbamate thiolate metal complex of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are the same or different and represent hydrogen, and unsubstituted or substituted alkyl, akenyl, aryl, alkoxy, and heteroaryl groups; M is a heavy metal selected from the group consisting of arsenic, bismuth, gallium, manganese, selenium, zinc, titanium, vanadium, chromium, iron, cobalt, nickel, copper, silver, silver, and gold; An is an anion selected from the group consisting of chloride, bromide, iodide, acetate and low molecular weight organic or inorganic pharmaceutically acceptable anions; n is the valence of the metal.  
     
     
         13 . The method according to  claim 12  wherein said dithiocarbamate thiolate metal complex is in the form of a pharmaceutically acceptable salt.  
     
     
         14 . The method according to  claim 12  wherein said dithiocarbamate thiolate metal complex is administered in a dosage of between about 125 to about 1000 mg per day of body weight.  
     
     
         15 . The method according to  claim 12  wherein said dithiocarbamate thiolate metal complex is administered in a dosage of between about 250 to about 500 mg per day.  
     
     
         16 . The method according to  claim 12  wherein said dithiocarbamate thiolate metal complex is administered parenterally.  
     
     
         17 . The method according to  claim 12  wherein said dithiocarbamate thiolate anion is administered orally.  
     
     
         18 . The method according to  claim 12  wherein said metal complex is administered separately as a chelate with an organic anion.  
     
     
         19 . The method according to  claim 18  wherein said an organic anion is selected from the group consisting of citrate, acetate, glyconate, glycinate, propionate and lactate.  
     
     
         20 . A method of reducing hypoxic or ischemic damage to the cardiovascular system of a human comprising administering a therapeutically effective amount of a dithiocarbamate thiolate anion of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are the same or different and represent hydrogen, and unsubstituted or substituted alkyl, akenyl, aryl, alkoxy, and heteroaryl groups; M is an alkali metal selected from the group consisting of from the group consisting of sodium, potassium, calcium, magnesium, barium, and lithium; and n is the valence of the alkali metal.  
     
     
         21 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is in the form of a pharmaceutically acceptable salt.  
     
     
         22 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is administered in a dosage of between about 125 to about 1000 mg per day of body weight.  
     
     
         23 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is administered in a dosage of between about 250 to about 500 mg per day for disulfiram.  
     
     
         24 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is administered parenterally.  
     
     
         25 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is administered orally.  
     
     
         26 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is administered in combination with a metal complex that includes an ion selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc.  
     
     
         27 . The method according to  claim 26  wherein said metal complex is administered as a chelate with an organic anion.  
     
     
         28 . The method according to  claim 27  wherein said an organic anion is selected from the group consisting of citrate, acetate, glyconate, glycinate, propionate and lactate.  
     
     
         29 . The method according to  claim 20  wherein said dithiocarbamate thiolate anion is administered in combination with a metal chelate that includes an ion selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc.  
     
     
         30 . A method of reducing hypoxic or ischemic damage to the cardiovascular system of a human comprising administering a therapeutically effective amount of a dithiocarbamate thiolate metal complex of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are the same or different and represent hydrogen, and unsubstituted or substituted alkyl, akenyl, aryl, alkoxy, and heteroaryl groups; M is a heavy metal selected from the group consisting of arsenic, bismuth, gallium, manganese, selenium, zinc, titanium, vanadium, chromium, iron, cobalt, nickel, copper, silver, silver, and gold; An is an anion selected from the group consisting of chloride, bromide, iodide, acetate and low molecular weight organic or inorganic pharmaceutically acceptable anions; n is the valence of the metal.  
     
     
         31 . The method according to  claim 30  wherein said dithiocarbamate thiolate metal complex is in the form of a pharmaceutically acceptable salt.  
     
     
         32 . The method according to  claim 30  wherein said dithiocarbamate thiolate metal complex is administered in a dosage of between about 125 to about 1000 mg per day of body weight.  
     
     
         33 . The method according to  claim 30  wherein said dithiocarbamate thiolate metal complex is administered in a dosage of between about 250 to about 500 mg per day for disulfiram.  
     
     
         34 . The method according to  claim 30  wherein said dithiocarbamate thiolate metal complex is administered parenterally.  
     
     
         35 . The method according to  claim 30  wherein said dithiocarbamate thiolate metal complex is administered orally.  
     
     
         36 . The method according to  claim 30  wherein said metal complex is administered separately as a chelate with an organic anion.  
     
     
         37 . The method according to  claim 36  wherein said an organic anion is selected from the group consisting of citrate, acetate, glyconate, glycinate, propionate and lactate.  
     
     
         38 . A method for treating asthma or arthritis in humans comprising administering a therapeutically effective amount of a dithiocarbamate thiolate anion of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are the same or different and represent hydrogen, and unsubstituted or substituted alkyl, akenyl, aryl, alkoxy, and heteroaryl groups; M is an alkali metal selected from the group consisting of from the group consisting of sodium, potassium, calcium, magnesium, barium, and lithium; and n is the valence of the alkali metal.  
     
     
         39 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is in the form of a pharmaceutically acceptable salt.  
     
     
         40 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is administered in a dosage of between about 125 to about 1000 mg per day of body weight.  
     
     
         41 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is administered in a dosage of between about 250 to about 500 mg per day for disulfiram.  
     
     
         42 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is administered parenterally.  
     
     
         43 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is administered orally.  
     
     
         44 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is administered in combination with a metal complex that includes an ion selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc.  
     
     
         45 . The method according to  claim 44  wherein said metal complex is administered separately as a chelate with an organic anion.  
     
     
         46 . The method according to  claim 45  wherein said an organic anion is selected from the group consisting of citrate, acetate, glyconate, glycinate, propionate and lactate.  
     
     
         47 . The method according to  claim 38  wherein said dithiocarbamate thiolate anion is administered in combination with a metal chelate that includes an ion selected from the group consisting of arsenic, bismuth, cobalt, copper chromium, gallium, gold iron, manganese, nickel, silver, titanium, vanadium, selenium and zinc.  
     
     
         48 . A method for treating asthma or arthritis in humans comprising administering a therapeutically effective amount of a dithiocarbamate thiolate anion of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  and R 3  are the same or different and represent hydrogen, and unsubstituted or substituted alkyl, akenyl, aryl, alkoxy, and heteroaryl groups; M is a heavy metal selected from the group consisting of arsenic, bismuth, gallium, manganese, selenium, zinc, titanium, vanadium, chromium, iron, cobalt, nickel, copper, silver, silver, and gold; An is an anion selected from the group consisting of chloride, bromide, iodide, acetate and low molecular weight organic or inorganic pharmaceutically acceptable anions; n is the valence of the metal.  
     
     
         49 . The method according to  claim 48  wherein said dithiocarbamate thiolate metal complex is in the form of a pharmaceutically acceptable salt.  
     
     
         50 . The method according to  claim 48  wherein said dithiocarbamate thiolate metal complex is administered in a dosage of between about 125 to about 1000 mg per day of body weight.  
     
     
         51 . The method according to  claim 48  wherein said dithiocarbamate thiolate metal complex is administered in a dosage of between about 250 to about 500 mg per day for disulfiram.  
     
     
         52 . The method according to  claim 48  wherein said dithiocarbamate thiolate metal complex is administered parenterally.  
     
     
         53 . The method according to  claim 48  wherein said dithiocarbamate thiolate metal complex is administered orally.  
     
     
         54 . The method according to  claim 48  wherein said metal complex is administered separately as a chelate with an organic anion.  
     
     
         55 . The method according to  claim 54  wherein said an organic anion is selected from the group consisting of citrate, acetate, glyconate, glycinate, propionate and lactate.